Device and method for delivery of a medicament

ABSTRACT

The disclosure relates to a method of enhancing nicotine or other medicament concentrations in a gaseous carrier. The methods are adaptable to the delivery of nicotine or other medicaments for therapeutic effect in various diseases, in particular nicotine for tobacco product use cessation, substitution and/or harm reduction. The disclosure further relates various devices and device design principles for practicing these methods.

TECHNICAL FIELD

The invention relates to devices and methods for delivering a medicamentto a user. More particularly, the invention relates to devices andmethods for delivering an aerosol of a medicament to a user's lungs.

BACKGROUND ART

Pulmonary drug delivery systems have been used for decades to delivermedicaments for the treatment of respiratory disorders. The principlebehind pulmonary drug delivery is aerosolization of drug compounds to bedelivered to bronchioles and alveoli. Despite facing challenges likeparticle size optimization and degradation, a number of companies havedeveloped technologies to deliver treatments for diabetes, migraine,osteoporosis and cancer.

The available delivery systems include metered dose inhalers (MDIs), drypowder inhalers (DPIs), and nebulizers. MDIs were among the first to beintroduced in the United States in the mid 1950s. The HFA-based(pressurized) MDI was introduced in the United States in 1995. AlthoughDPIs were introduced in the 1970s, their use has been limited due to theoverwhelming dominance of MDIs. Nebulizers are generally used withinhospital settings. Technological advances within the pulmonary drugdelivery technologies markets are taking place in non-CFC-based MDIs,DPIs, and liquid-based inhalers (LBIs).

Many preclinical and clinical studies have demonstrated that pulmonarydelivery of medicaments is an efficient method for the treatment of bothrespiratory and systemic diseases. The many advantages of pulmonarydelivery are well recognized and include rapid onset, patientself-administration, reduced side-effects, ease of delivery byinhalation, and the elimination of needles.

Nevertheless, methods for the administration of most medicaments havenot significantly deviated from delivery via the traditionalintravenous/intramuscular and oral routes to include pulmonary deliveryvia inhalation. The use of pulmonary delivery has been limited mainly tothe administration of medicaments for the treatment of asthma.

It has been reported that in order to deliver a powder directly into thelower respiratory regions the powder should generally have a particlesize of less than 5 μm. Further, powders in the 5-10 μm range have beenfound not to penetrate as deeply and instead tend to stimulate the upperrespiratory tract regions.

When manufacturing drug formulations for dry powder inhalers (DPIs), themedicament must first be milled to obtain an acceptable particle sizefor pulmonary delivery. This micronization step can cause problemsduring manufacture. For example, the heat produced during milling cancause degradation of the medicament. Additionally, metal can rub offsome mills and contaminate the medicament. Furthermore, due to the smallsize of the particles, dry powder formulations tend to agglomerate,especially in the presence of moisture.

Agglomeration results in low flowability of the particles whichdiminishes the efficacy of the dry powder formulation. As a result,careful supervision is required during milling, blending, powder flow,filling and even administration to ensure that the dry powder aerosolsare properly delivered.

Thus, there is a need for new methods to prepare aerosols for medicamentdelivery. The present disclosure describes in part a method forcombining nicotine or other medicaments with a delivery enhancingcompound in a gaseous stream to generate an aerosol for pulmonarydelivery, without the need for excipients or other additives includingsolvents.

DISCLOSURE OF INVENTION Brief Summary of the Invention

In some embodiments, the disclosure relates to a method of deliveringnicotine to a subject by inhalation, the method comprising the steps of:

-   -   a) first placing a gaseous carrier comprising a delivery        enhancing compound in communication with a nicotine source        comprising the nicotine, and    -   b) second providing the gaseous carrier comprising the nicotine        to a subject.

In some embodiments, the disclosure relates to the method of paragraph[0010], further comprising the step of placing the gaseous carrier incommunication with a delivery enhancing compound source comprising thedelivery enhancing compound.

In some embodiments, the disclosure relates to the method of [0011],wherein the step of placing the gaseous carrier in communication withthe delivery enhancing compound source precedes the step of placing thegaseous carrier comprising the delivery enhancing compound incommunication with the nicotine source.

In some embodiments, the disclosure relates to the method of [0010],[0011], or [0012], wherein the delivery enhancing compound sourcecomprises a plurality of compartments comprising two or more precursorcompounds.

In some embodiments, the disclosure relates to the method of [0013],wherein the delivery enhancing compound comprises ammonium chloride andthe two or more precursor compounds include ammonia and hydrogenchloride.

In some embodiments, the disclosure relates to the methods of[0010]-[0013], or [0014], wherein the nicotine concentration in thegaseous carrier is increased relative to the nicotine concentration thatwould be contained in the gaseous carrier without the delivery enhancingcompound.

In some embodiments, the disclosure relates to the methods of[0010]-[0014], or [0015], wherein the delivery enhancing compoundcomprises an acid.

In some embodiments, the disclosure relates to the method of [0016],wherein the acid is an organic acid.

In some embodiments, the disclosure relates to the method of [0017],wherein the organic acid has a greater vapor pressure than nicotine baseat a given temperature.

In some embodiments, the disclosure relates to the method of [0018],wherein the given temperature is 25, 30, 40, 45, 70 or 100 degrees C.

In some embodiments, the disclosure relates to the methods of[0016]-[0018], or [0019] wherein the acid is selected from the groupconsisting of 3-Methyl-2-oxovaleric acid, Pyruvic acid, 2-Oxovalericacid, 4-Methyl-2-oxovaleric acid, 3-Methyl-2-oxobutanoic acid,2-Oxooctanoic acid and combinations thereof.

In some embodiments, the disclosure relates to the methods of[0010]-[0019], or [0020], wherein the delivery enhancing compoundinteracts with the nicotine to form particles.

In some embodiments, the disclosure relates to the method of [0021],wherein the particles are less than 6 microns in Mass Median AerodynamicDiameter.

In some embodiments, the disclosure relates to the method of [0021],wherein the particles are less than 1 micron in Mass Median AerodynamicDiameter.

In some embodiments, the disclosure relates to the method of [0021],wherein at least some of the particles are between 0.5 and 5 microns inMass Median Aerodynamic Diameter.

In some embodiments, the disclosure relates to the methods of[0010]-[0023], or [0024], further comprising the step of increasing thetemperature of the delivery enhancing compound, the delivery enhancingcompound source, the nicotine, the nicotine source and/or the gaseouscarrier.

In some embodiments, the disclosure relates to the method of [0025],wherein the temperature is increased to at least 30 degrees Celsius.

In some embodiments, the disclosure relates to the methods of[0010]-[0025], or [0026], wherein the gaseous carrier comprises at least20 micrograms of nicotine in a volume of gaseous carrier provided to thesubject.

In some embodiments, the disclosure relates to the method of [0027],wherein the volume of gaseous carrier delivered to the subject isprovided as a single volume.

In some embodiments, the disclosure relates to a method of tobaccoproduct use cessation comprising one or more of the methods of[0010]-[0027], or [0028] and further comprising a delivery to thesubject of a therapeutically effective amount of nicotine to at leastpartially replace nicotine derived from a tobacco product.

In some embodiments, the disclosure relates to a method of treating adisease for which nicotine is therapeutically beneficial comprising oneor more of the methods of [0010]-[0027], or [0028], wherein atherapeutically effective amount of nicotine is provided to the subject.

In some embodiments, the disclosure relates to the method of [0030],wherein the disease is selected from the group consisting of nicotineaddiction, obesity, Alzheimer's Disease, Parkinson's Disease, UlcerativeColitis, Multiple Sclerosis and combinations thereof.

In some embodiments, the disclosure relates to a method of tobaccoproduct substitution comprising delivering nicotine to a subject by themethods of [0010]-[0027], or [0028] to substitute for nicotine derivedfrom a tobacco product.

In some embodiments, the disclosure relates to a method of tobaccoproduct harm reduction comprising delivering nicotine to a subject bythe methods of [0010]-[0027], or [0028] to replace nicotine derived froma tobacco product.

In some embodiments, the disclosure relates to a device configured to becapable of carrying out the methods of [0010]-[0032], or [0033].

In some embodiments, the disclosure relates to a device for deliveringnicotine to a subject, the device comprising a housing, the housingcomprising:

-   -   a) an inlet and an outlet in communication with each other and        adapted so that a gaseous carrier may pass into the housing        through the inlet, through the housing and out of the housing        through the outlet, the device comprising in series from inlet        to outlet:    -   b) a first internal area in communication with the inlet, the        first internal area comprising a delivery enhancing compound        source,    -   c) a second internal area in communication with the first        internal area, the second internal area comprising a nicotine        source, and    -   d) optionally, a third internal area in communication with the        second internal area and the outlet.

In some embodiments, the disclosure relates to the device of [0035]wherein a partial vacuum at the outlet is capable of pulling the gaseouscarrier through the inlet, the first compartment, the secondcompartment, the third compartment, when present, and then through theoutlet.

In some embodiments, the disclosure relates to the device of [0035] or[0036] wherein the delivery enhancing compound source comprises anadsorption element with the delivery enhancing compound adsorbed thereonand/or wherein the nicotine source comprises an adsorption element withthe nicotine adsorbed thereon.

In some embodiments, the disclosure relates to the device of [0037]wherein the adsorption element or elements comprises at least one ofglass, aluminum, Polyethylene Terephthalate (PET), PolybutyleneTerephthalate (PBT), Polytetrafluoroethylene (PTFE or TEFLON®), ExpandedPolytetrafluoroethylene (ePTFE) (ePTFE is described for example in U.S.Pat. No. 4,830,643), and BAREX®.

In some embodiments, the disclosure relates to the devices of[0035]-[0037], or [0038], further comprising a first reservoir incommunication with the first internal area, the first reservoircomprising the delivery enhancing compound.

In some embodiments, the disclosure relates to the devices of[0035]-[0038], or [0039], further comprising a second reservoir incommunication with the second internal area, the second reservoircomprising nicotine.

In some embodiments, the disclosure relates to the devices of[0035]-[0039], or [0040], comprising the third internal area, the thirdinternal area comprising a third internal area element.

In some embodiments, the disclosure relates to the device of [0041],wherein the third internal area element comprises a purifying agent.

In some embodiments, the disclosure relates to the device of [0042],wherein the purifying agent comprises activated charcoal.

In some embodiments, the disclosure relates to the devices of [0041],[0042], or [0043], wherein the third internal area element comprises aflavoring agent.

In some embodiments, the disclosure relates to the devices of[0041]-[0043], or [0044], where the third internal area elementcomprises a medicament.

In some embodiments, the disclosure relates to the device of [0045],wherein the medicament comprises nicotine.

In some embodiments, the disclosure relates to the devices of[0035]-[0045], or [0046], wherein the housing simulates a tobaccosmoking product.

In some embodiments, the disclosure relates to the device of [0047],wherein the tobacco smoking product is a cigarette.

In some embodiments, the disclosure relates to the devices of[0035]-[0045], or [0046], wherein the housing simulates a pharmaceuticalinhalation device.

In some embodiments, the disclosure relates to the device of [0049],wherein the simulated pharmaceutical inhalation device is selected formthe group consisting of a metered dose inhaler, a pressurized metereddose inhaler, a dry powder inhaler, a nebulizer, and a liquid basedinhaler.

In some embodiments, the disclosure relates to a method of increasing anicotine concentration in a gaseous carrier comprising a step of placingthe gaseous carrier comprising a delivery enhancing compound incommunication with a nicotine source comprising the nicotine.

In some embodiments, the disclosure relates to the method of [0051],further comprising the step of placing the gaseous carrier incommunication with a delivery enhancing compound source comprising thedelivery enhancing compound.

In some embodiments, the disclosure relates to the method of [0052],wherein the step of placing the gaseous carrier in communication withthe delivery enhancing compound source precedes the step of placing thegaseous carrier comprising the delivery enhancing compound incommunication with the nicotine source.

In some embodiments, the disclosure relates to the method of [0051],[0052], or [0053], wherein the delivery enhancing compound sourcecomprises a plurality of compartments comprising two or more precursorcompounds.

In some embodiments, the disclosure relates to the method of [0054],wherein the delivery enhancing compound comprises ammonium chloride andthe two or more precursor compounds include ammonia and hydrogenchloride.

In some embodiments, the disclosure relates to the method of[0051]-[0054], or [0055], wherein the nicotine concentration in thegaseous carrier is increased relative to the nicotine concentration thatwould be contained in the gaseous carrier without the delivery enhancingcompound.

In some embodiments, the disclosure relates to the method of[0051]-[0055], or [0056], wherein the delivery enhancing compoundcomprises an acid.

In some embodiments, the disclosure relates to the method of [0057],wherein the acid is an organic acid.

In some embodiments, the disclosure relates to the method of [0058],wherein the organic acid has a greater vapor pressure than nicotine at agiven temperature.

In some embodiments, the disclosure relates to the method of [0059],wherein the given temperature is 25, 30, 40, 45, 70 or 100 degreesCelsius.

In some embodiments, the disclosure relates to the method of [0057],wherein the acid is selected from the group consisting of3-Methyl-2-oxovaleric acid, Pyruvic acid, 2-Oxovaleric acid,4-Methyl-2-oxovaleric acid, 3-Methyl-2-oxobutanoic acid, 2-Oxooctanoicacid and combinations thereof.

In some embodiments, the disclosure relates to the method of[0051]-[0060], or [0061], wherein the delivery enhancing compoundinteracts with the nicotine to form particles.

In some embodiments, the disclosure relates to the method of [0062],wherein some or all of the particles are less than 6 microns in MassMedian Aerodynamic Diameter.

In some embodiments, the disclosure relates to the method of [0062],wherein some or all of the particles are less than 1 micron in MassMedian Aerodynamic Diameter.

In some embodiments, the disclosure relates to the method of [0062],wherein at least some of the particles are between 0.5 and 5 microns inMass Median Aerodynamic Diameter.

In some embodiments, the disclosure relates to the method of[0051]-[0064], or [0065], further comprising the step of increasing thetemperature of the delivery enhancing compound, the delivery enhancingcompound source, the nicotine, the nicotine source and/or the gaseouscarrier.

In some embodiments, the disclosure relates to the method of [0066],wherein the temperature is increased to at least 30 degrees Celsius.

In some embodiments, the disclosure relates to the method of [0067],wherein the temperature is elevated by a plurality of heating steps.

In some embodiments, the disclosure relates to a nicotine for tobaccoproduct use cessation, the nicotine delivered by the method of[0051]-[0067], or [0068], further comprising the step of providing thegaseous carrier to a subject after the step of placing the gaseouscarrier comprising the delivery enhancing compound in communication withthe nicotine source.

In some embodiments, the disclosure relates to the nicotine of [0069],wherein the gaseous carrier comprises at least 20 micrograms of nicotinein a volume of gaseous carrier provided to the subject.

In some embodiments, the disclosure relates to the nicotine of [0070],wherein the volume of gaseous carrier delivered to the subject isprovided as a single volume.

In some embodiments, the disclosure relates to a nicotine for tobaccoproduct harm reduction, the nicotine delivered by the method of[0051]-[0067], or [0068], further comprising the step of providing thegaseous carrier to a subject after the step of placing the gaseouscarrier comprising the delivery enhancing compound in communication withthe nicotine source.

In some embodiments, the disclosure relates to the nicotine of [0072],wherein the gaseous carrier comprises at least 20 micrograms of nicotinein a volume of gaseous carrier provided to the subject.

In some embodiments, the disclosure relates to the nicotine of [0073],wherein the volume of gaseous carrier delivered to the subject isprovided as a single volume.

In some embodiments, the disclosure relates to a nicotine for tobaccoproduct substitution, the nicotine delivered by the method of[0051]-[0067], or [0068], further comprising the step of providing thegaseous carrier to a subject after the step of placing the gaseouscarrier comprising the delivery enhancing compound in communication withthe nicotine source.

In some embodiments, the disclosure relates to the nicotine of [0075],wherein the gaseous carrier comprises at least 20 micrograms of nicotinein a volume of gaseous carrier provided to the subject.

In some embodiments, the disclosure relates to the nicotine of [0076],wherein the volume of gaseous carrier delivered to the subject isprovided as a single volume.

In some embodiments, the disclosure relates to a nicotine for thetreatment of a disease selected from the group consisting of nicotineaddiction, obesity, Alzheimer's Disease, Parkinson's Disease, UlcerativeColitis, Multiple Sclerosis and combinations thereof, the nicotinedelivered by the method of [0051]-[0067], or [0068], further comprisingthe step of providing the gaseous carrier to a subject after the step ofplacing the gaseous carrier comprising the delivery enhancing compoundin communication with the nicotine source.

In some embodiments, the disclosure relates to a device configured to becapable of carrying out a) the method of [0051]-[0067], or [0068];and/or b) configured to be capable of delivering the nicotine of[0069]-[0077], or [0078].

In some embodiments, the disclosure relates to a use of nicotine for themanufacture of a medicament for delivery by the method of [0051]-[0067],or [0068].

In some embodiments, the disclosure relates to a use of nicotine for themanufacture of a medicament for tobacco product use cessation fordelivery by the method of [0051]-[0067], or [0068].

In some embodiments, the disclosure relates to a use of nicotine for themanufacture of a medicament for tobacco product harm reduction fordelivery by the method of [0051]-[0067], or [0068].

In some embodiments, the disclosure relates to a use of nicotine for themanufacture of a medicament for tobacco product substitution fordelivery by the method of [0051]-[0067], or [0068].

In some embodiments, the disclosure relates to a use of nicotine for themanufacture of a medicament for the treatment of a disease selected fromthe group consisting of nicotine addiction, obesity, Alzheimer'sDisease, Parkinson's Disease, Ulcerative Colitis, Multiple Sclerosis andcombinations thereof, the nicotine delivered by the method of[0051]-[0067], or [0068], further comprising the step of providing thegaseous carrier to a subject after the step of placing the gaseouscarrier comprising the delivery enhancing compound in communication withthe nicotine source.

In some embodiments, the disclosure relates to a method for delivering amedicament to a user, the method comprising:

-   -   passing a gaseous stream over a first substance to create a        first vapor-containing gaseous stream;    -   passing the first vapor-containing gaseous stream over a second        substance to create particles in the gaseous stream; and    -   delivering the gaseous stream containing the particles to a        user.

In some embodiments, the disclosure relates to the method of [0085],wherein the step of creating the first vapor-containing gaseous streamcomprises capturing a vapor of the first substance in the gaseousstream.

In some embodiments, the disclosure relates to the method of [0085] or[0086], wherein the step of creating particles comprises contacting avapor of the second substance with the first vapor-containing gaseousstream.

In some embodiments, the disclosure relates to the method of [0085],[0086], or [0087], wherein the step of creating the particles comprisesan interaction between the first and second substances.

In some embodiments, the disclosure relates to the method of [0088],where said interaction comprises an acid-base reaction.

In some embodiments, the disclosure relates to the method of[0085]-[0088], or [0089], where the first and second substances arevolatile substances.

In some embodiments, the disclosure relates to the method of [0090],wherein the first substance is more volatile at ambient temperature thanthe second substance.

In some embodiments, the disclosure relates to the method of[0085]-[0090], or [0091], wherein one of the first substance and/or thesecond substance comprises a nicotine.

In some embodiments, the disclosure relates to the method of [0092],wherein the nicotine comprises free base nicotine.

In some embodiments, the disclosure relates to the method of[0085]-[0092], or [0093], wherein the particles comprisenicotine-containing particles.

In some embodiments, the disclosure relates to the method of[0085]-[0093], or [0094], wherein the gaseous stream delivered to a usercontains more than 20 micrograms of nicotine-containing particles.

In some embodiments, the disclosure relates to the method of[0085]-[0094], or [0095], wherein the particles comprise nicotine saltparticles.

In some embodiments, the disclosure relates to the method of[0085]-[0095], or [0096], wherein the first substance comprises an acid.

In some embodiments, the disclosure relates to the method of [0097],wherein the acid comprises pyruvic acid.

In some embodiments, the disclosure relates to the method of[0085]-[0097], or [0098], wherein the particles comprise nicotinepyruvate.

In some embodiments, the disclosure relates to the method of [0097],wherein the acid comprises 3-methyl-2-oxobutanoic acid.

In some embodiments, the disclosure relates to the method of[0085]-[0099], or [0100], wherein the particles comprise nicotine3-methyl-2-oxobutanoate.

In some embodiments, the disclosure relates to the method of[0085]-[0100], or [0101], wherein at least some of the particles arevisible particles.

In some embodiments, the disclosure relates to the method of[0085]-[0101], or [0102], wherein at least some of the particles aredelivered to the lungs of the user.

In some embodiments, the disclosure relates to the method of[0085]-[0102], or [0103], wherein the particles are less than 6 micronsin diameter.

In some embodiments, the disclosure relates to the method of[0085]-[0103], or [0104], wherein at least some of the particles arebetween 0.5 and 5 microns in diameter.

In some embodiments, the disclosure relates to the method of[0010]-[0027], or [0028]; or the method of [0051]-[0067], or [0068]; orthe use of [0080] wherein a medicament listed at [0132], such as acompound identified by numbers 1-66 in [0132], is used instead, of or inaddition to, the nicotine recited in [0010]-[0027], or [0028];[0051]-[0067], or [0068]; or [0080].

In some embodiments, the disclosure relates to the device of[0035]-[0049], or [0050] wherein the device is adapted to deliver amedicament listed in [0132], such as a compound identified by numbers1-66 in [0132], instead of, or in addition to, the nicotine.

In some embodiments, the disclosure relates to use of a medicament of[0132], such as a compound identified by numbers 1-66 in [0132], fordelivery by the methods of [0010]-[0027], or [0028]; or [0051]-[0067],or [0068] for treatment of a disease for which the medicament istherapeutically beneficial.

The foregoing has outlined rather broadly the features and technicaladvantages of the present invention in order that the detaileddescription of the invention that follows may be better understood.Additional features and advantages of the invention will be describedhereinafter which form the subject of the claims of the invention. Itshould be appreciated by those skilled in the art that the conceptionand specific embodiment disclosed may be readily utilized as a basis formodifying or designing other structures for carrying out the samepurposes of the present invention. It should also be realized by thoseskilled in the art that such equivalent constructions do not depart fromthe spirit and scope of the invention as set forth in the appendedclaims. The novel features which are believed to be characteristic ofthe invention, both as to its organization and method of operation,together with further objects and advantages will be better understoodfrom the following description when considered in connection with theaccompanying figures. It is to be expressly understood, however, thateach of the figures is provided for the purpose of illustration anddescription only and is not intended as a definition of the limits ofthe present invention.

BRIEF DESCRIPTION OF DRAWINGS

For a more complete understanding of the present invention, reference isnow made to the following descriptions taken in conjunction with theaccompanying drawing, in which:

FIG. 1 a perspective view of the exterior of an exemplary deliverydevice simulating a cigarette;

FIG. 2 a perspective view of the interior of an exemplary deliverydevice simulating a cigarette;

FIG. 3 a perspective view of the exemplary delivery device from FIGS. 1and 2 in use;

FIG. 4 a sectional view of the subcomponents of an exemplary deliverydevice showing the assembly stages and final configuration of thecomponents for device use;

FIG. 5 a perspective view of various source elements for providing thenicotine or other medicament and the delivery enhancing compound;

FIG. 6 a sectional view of the subcomponents of an exemplary deliverydevice showing reusable and disposable portions;

FIG. 7 a sectional view of the subcomponents of a reusable exemplarydelivery device showing the device and a recharging unit for supplyingnicotine or other medicament and the delivery enhancing compound;

FIG. 8 a sectional view of a reusable exemplary delivery device showingthe device and a perspective view of a recharging unit for supplyingnicotine or other medicament and the delivery enhancing compound; and

FIG. 9 a sectional view of a reusable exemplary delivery device showingthe device and a recharging unit; 9A shows the recharging unit alone, 9Bshows the delivery device seated in the recharging unit and 9C shows thedelivery device after compression of the metered dose pumps of therecharging unit for resupplying nicotine or other medicament and thedelivery enhancing compound;

FIG. 10A a sectional view of an exemplary delivery device with a heatingcomponent therein shown in perspective view as a separate component; 10Ban exemplary delivery device having an external heating unit into whichthe delivery device is seated for temperature control of the deviceand/or its constituents;

FIG. 11 a sectional view of an exemplary device simulates a metered doseinhaler commonly used for pharmaceutical delivery of inhaledmedicaments;

FIG. 12 a sectional view of an exemplary device simulates a metered doseinhaler commonly used for pharmaceutical delivery of inhaledmedicaments;

FIG. 13 a sectional view of an exemplary device simulates a metered doseinhaler commonly used for pharmaceutical delivery of inhaledmedicaments;

FIG. 14 a sectional view of an exemplary device simulates a metered doseinhaler commonly used for pharmaceutical delivery of inhaledmedicaments;

FIG. 15 a sectional view of an exemplary device simulates a metered doseinhaler commonly used for pharmaceutical delivery of inhaledmedicaments.

DETAILED DESCRIPTION

“Particle” as used herein may refer to a liquid droplet, a solidparticulate or a combination of both, such as a liquid droplet nucleatedby a solid particulate.

“Therapeutically effective amount” as used herein may refer to aconcentration or amount of nicotine or other medicament which achieves atherapeutic effect in a subject, generally a human subject. The subjecthas an improvement in a disease or medically defined condition. Theimprovement is any improvement or remediation of the symptoms associatedwith the disease. The improvement is an observable or measurableimprovement. Thus, one of skill in the art realizes that a treatment mayimprove the disease condition, but may not be a complete cure for thedisease. The therapeutic effect in some embodiments may includereduction or elimination of nicotine craving in a subject sufferingnicotine addiction or in a subject experiencing nicotine use withdrawalsymptoms.

To aid in the understanding of the concepts of the present invention,embodiments will be described herein with reference to devices andmethods for nicotine delivery. It will be appreciated by one of ordinaryskill in the art that the medicaments listed at [0132] may be used inplace of or in addition to the nicotine according to the teachingsherein.

The methods described herein relate to a surprising discovery regardingthe dose of nicotine obtained from nicotine delivery devices. Theinventors have unexpectedly identified methods for increasing the doseof nicotine delivered to a subject by inhalation. The importance of thisdiscovery lies in an improved ability to substitute for the nicotinedelivery subjects experience while smoking cigarettes and similartobacco products. With improved nicotine delivery profiles, subjectsapplying the methods described herein will be provided with superiornicotine replacement therapy during attempts at smoking cessation, harmreduction and/or substitution. With the continued global problem ofsmoking related health issues, the methods described herein address acritical need in medical efforts to assist smokers in quitting.

Without desiring to be bound by theory, it is believed that passing thevapor of a volatile first substance (i.e. a delivery enhancing compound)over a nicotine source results in the formation of particles in a liquidor solid state, which subsequently allows more of the nicotine toevaporate and combine with the first substance, generating furtherparticles. The amount of particle formation (mass delivered) at a giventemperature would be greater than that formed when the vapor of nicotineis passed over a second volatile substance. Similarly, the amount ofparticle formation at a given temperature would be greater than thatformed when the vapors of the two substances are combined in a parallelmixing apparatus (as disclosed in prior art), due to the amount ofparticle formation being limited by the volatility of the less volatilesubstance and to the dilution of the active substance by mixing with thevolume of gas containing the other substance. Also, allowing sequentialpassing of one substance over a second substance may allow for a moreefficient combination of the two substances than parallel mixing asdisclosed in prior art. Another possibility is that the interactionbetween the first and second substances is an exothermic process. Inother words, energy is released in the form of heat as a result of theexothermic interaction. Without desiring to be bound by theory, it isbelieved that the heat released may enhance the evaporation of thenicotine.

In some embodiments, the methods involve the step of bringing a gaseouscarrier in communication with a nicotine source. The gaseous carrier inthese embodiments contains a delivery enhancing compound capable ofincreasing the amount of nicotine in the gaseous carrier, relative tothe amount of nicotine that would be in the gaseous carrier lacking thedelivery enhancing compound. In some embodiments, the delivery enhancingcompound is capable of reacting with nicotine base or other medicamentto form a salt. In particular embodiments, the delivery enhancingcompound is capable of reacting with nicotine base to form saltparticles. In preferred embodiments, the particles are less than 6micrometers, more preferably less than 1 micrometer, in Mass MedianAerodynamic Diameter. (For Mass Median Aerodynamic Diameterdeterminations, see Katz I M, Schroeter J D, Martonen T B, Factorsaffecting the deposition of aerosolized insulin, Diabetes technology &Therapeutics, vol. 3 (3), 2001, pp 387-397, incorporated by referencefor this teaching).

The methods disclosed herein may be adapted for use with a variety ofother medicaments having similar biophysical and/or chemical propertiesto nicotine. The following compounds are aliphatic or aromatic,saturated or unsaturated nitrogenous bases (nitrogen containing alkalinecompounds) in which a nitrogen atom is present in a heterocyclic ring orin an acyclic chain (substitution). In addition, the compounds have beenselected based on melting point (below 150° C.) or boiling point (below300° C.) that are expected to favor volatilization:

Medicaments - other than Nicotine 1. 7-Hydroxymitragynine 2. Arecoline3. Atropine 4. Bupropion 5. Cathine (D- norpseudoephedrine) 6.Chlorpheneramine 7. Dibucaine 8. Dimemorphan 9. Dimethyltryptamine 10.Diphenhydramine 11. Ephedrine 12. Hordenine 13. Hyoscyamine 14.Isoarecoline 15. Levorphanol 16. Lobeline 17. Mesembrine 18. Mitragynine19. Muscarine 20. Procaine 21. Pseudo ephedrine 22. Pyrilamine 23.Raclopride 24. Ritodrine 25. Scopolamine 26. Sparteine (Lupinidine) 27.Ticlopidine Tobacco Smoke Constituents: 28. 1,2,3,4-Tetrahydroisoquinolines 29. Anabasine 30. Anatabine 31. Cotinine 32.Myosmine 33. Nicotrine 34. Norcotinine 35. Nornicotine Anti-asthmaticdrugs 36. Orciprenaline 37. Propranolol 38. Terbutaline Anti-anginadrugs 39. Nicorandil 40. Oxprenolol 41. Verapamil Antiarrhythmic drugs42. Lidocaine Nicotinic receptor agents A. Nicotinic agonist 43.Epibatidine 44. 5-(2R)-azetidinylmethoxy)- 2-chloropyridine (ABT-594)45. (S)-3-methyl-5-(1-methyl-2- pyrrolidinyl)isoxazole (ABT 418) 46.(±)-2-(3-Pyridinyl)-1- azabicyclo[2.2.2]octane (RJR-2429) B. Nicotinicantagonist: 47. Methyllycacotinine 48. Mecamylamine C. Acetylcholinesterase inhibitors 49. Galantamine 50. Pyridostigmine 51.Physostigmine 52. Tacrine MAO-inhibitors 53. 5-Methoxy-N,N-dimethyltryptamine 54. 5-methoxy-α- methyltryptamine 55. Alpha-methyltryptamine 56. Iproclozide 57. Iproniazide 58. Isocarboxazide 59.Linezolid 60. Meclobemide 61. N,N- Dimethyltryptamine 62. Phenelzine 63.Phenyl ethylamine 64. Toloxatone 65. Tranylcypromine 66. Tryptamine

Gaseous Carrier and Source Thereof

The gaseous carrier may be any gas capable of containing nicotine baseand the delivery enhancing compound. One of skill in the art willreadily be able to select an appropriate gaseous carrier based on theintended use, form of nicotine and specific delivery enhancingcompound(s). In preferred embodiments, the gaseous carrier issubstantially inert with regard to the form of nicotine and/or thedelivery enhancing compound carried, at least for the time periodcontemplated for delivery to a subject. In some embodiments, the gaseouscarrier is ambient air. In other embodiments the gaseous carrier is asubstantially pure gas such as carbon dioxide or nitrogen gas, or ablend of such gases. In such embodiments, the gaseous carrier issupplied from a container designed to hold and deliver the gaseouscarrier in a manner to effect the methods described herein. For example,in embodiments using metered dose inhaler devices, the gaseous carriermay comprise Hydrofluorocarbons, which include Hydrofluoroalkanes (HFAs)as propellants. In some of these embodiments, the HFAs, are one or moreof HFA 134a and HFA 227.

Delivery Enhancing Compounds

Delivery enhancing compounds are those compounds capable of increasingthe total concentration of nicotine in a gaseous carrier when thegaseous carrier is placed in communication with a nicotine source.Nicotine has a vapor pressure of 0.04 mm Hg at 25° C. Delivery enhancingcompounds having a vapor pressure greater than nicotine at a giventemperature are preferred if ambient temperatures are used. Non-limitingexamples include inorganic acids such as hydrochloric, hydrobromic, orsulfuric acid, and organic acids including saturated and unsaturatedaliphatic acids, saturated and unsaturated alicyclic acids, aromaticacids (including heterocyclic aromatic), polycarboxylic acids, hydroxy,alkoxy, keto, and oxo acids, thioacids, amino acids, and each of thepreceding optionally substituted with one or more heteroatoms, includingbut not limited to halogens. In some embodiments, the delivery enhancingcompound is a carboxylic acid. In some of these embodiments, thecarboxylic acid is in the class termed “2-Oxo acids.” In some of theseembodiments, the carboxylic acid is in the class of a-Keto acids knownas “2-Keto acids.” In some of these embodiments, the acid is selectedfrom the group consisting of 3-Methyl-2-oxovaleric acid, Pyruvic acid,2-Oxovaleric acid, 4-Methyl-2-oxovaleric acid, 3-Methyl-2-oxobutanoicacid, 2-Oxooctanoic acid and combinations thereof. In some embodiments,the delivery enhancing compound forms solid particles, for example saltparticles. In other embodiments, the delivery enhancing compound forms aliquid droplet aerosol.

Alternatively, the delivery enhancing compound forms a particulateaerosol, the particles of which may, for example, adsorb or absorbnicotine base. In particular embodiments, the particulate aerosolincludes ammonium chloride salt particles. In embodiments comprisingnicotine particle formation or nicotine adsorption/absorption ontoparticles the particles formed are preferably less than 6 microns, morepreferably less than 5 microns or less than 1 micron in size.

Nicotine (or Other Medicament) Sources

Embodiments of a nicotine source use a compound comprising any chemicalcapable of providing a volatile form of nicotine such as nicotine baseor nicotine salts (e.g. nicotine-HCl, -ditartrate). Although more thanone form of nicotine can be used, free base nicotine is preferred. Thenicotine source may comprise other compounds such as antioxidants (BHA,BHT, ascorbate) for stabilizing the nicotine. In some embodiments,nicotine is adsorbed on an element to provide a nicotine source. Theadsorbed nicotine is held on the surface of a relatively inert material.Non-limiting examples of adsorption element materials include glass,stainless steel, aluminum, PET, PBT, PTFE, ePTFE, and BAREX®. Adsorptionis a process that occurs when a gas, liquid or solid solute accumulateson the surface of a solid or, more rarely, a liquid (adsorbent), forminga molecular or atomic film (the adsorbate). Physical adsorption istypically the result of van der Waals forces and electrostatic forcesbetween adsorbate molecules and the atoms which compose the adsorbentsurface. Thus adsorbents are characterized by surface properties such assurface area and polarity.

A large specific surface area is preferable for providing largeadsorption capacity, but the creation of a large internal surface areain a limited volume inevitably gives rise to large numbers of smallsized pores between adsorption surfaces. The size of the microporesdetermines the accessibility of adsorbate molecules to the internaladsorption surface, so the pore size distribution of micropores isanother important property for characterizing adsorptivity ofadsorbents. Surface polarity corresponds to affinity with polarsubstances such as water or alcohols. Polar adsorbents are thus called“hydrophilic” and aluminosilicates such as zeolites, porous alumina,silica gel or silica-alumina are examples of adsorbents of this type. Onthe other hand, non-polar adsorbents are generally “hydrophobic.”Carbonaceous adsorbents, polymer adsorbents and silicalite are typicalnon-polar adsorbents. These adsorbents have more affinity with oil orhydrocarbons than water. In some embodiments, the adsorbing surface alsowicks the adsorbed material by capillary action, when the adsorbent isin liquid form. Wicking occurs when the adhesive intermolecular forcesbetween the liquid and an adsorbing surface are stronger than thecohesive intermolecular forces inside the liquid. The effect causes aconcave meniscus to form where the substance is touching a verticaladsorbing surface. Adsorbing surfaces may be selected or designed towick hydrophilic or hydrophobic liquids.

In alternative embodiments, the nicotine source element can comprise anabsorbing (either porous or nonporous) material. Non-limiting examplesof nicotine source element materials include polyethylene (PE) andpolypropylene (PP).

A nicotine source may in some embodiments be or be in communication witha nicotine reservoir. In some embodiments, the reservoir contains avolume of nicotine in liquid form with the liquid reservoir incommunication with an adsorbing or absorbing nicotine source element. Inother embodiments, the nicotine reservoir is or forms part of thenicotine source element. A non-limiting example of such a combinationsource and reservoir would be a material (e.g., PE or PP) saturated withnicotine solution. In particular embodiments, the reservoir providessufficient nicotine solution to enable a delivery device to providetherapeutically effective doses of nicotine over a desired time frame.Non-limiting examples would be devices capable of delivering 0-100micrograms of nicotine per 35 cubic centimeter volume “puff” of gaseouscarrier for a desired number of puffs per day (e.g., 200) over a desirednumber of days (e.g., 1-7 days). In certain embodiments, the amount ofnicotine delivered is between 10 and 110, 20 and 100, 50 and 100, or 40and 60 micrograms of nicotine per 35 cubic centimeter volume “puff.”

Other medicaments listed in [0132] may be used in place of or inaddition to nicotine to form sources of medicament(s) using the sameprinciples applied to nicotine base as the example species above.

Delivery Enhancing Compound Sources

In some embodiments of the methods, the gaseous carrier is providedpre-combined with the delivery enhancing compound. Other embodiments ofthe methods described herein include a step of loading a gaseous carrierwith a delivery enhancing compound prior to or concurrently with passageof the gaseous carrier over the nicotine source. In embodimentsencompassing a step of loading gaseous carrier with a delivery enhancingcompound, the delivery enhancing compound is generally provided in theform of a delivery enhancing compound source. The gaseous carrier inthese embodiments is generally brought into direct communication withthe delivery enhancing compound source such that the delivery enhancingcompound may enter the gaseous carrier from the delivery enhancingcompound source. In some embodiments, delivery enhancing compoundsources comprise a delivery enhancing compound source element containingmaterials which adsorb or absorb the delivery enhancing compound.Delivery enhancing compound source element materials will generally beinert with respect to the delivery enhancing compound. In someembodiments, the delivery enhancing compound is an acid as describedabove. Non-limiting examples of adsorption element materials for suchembodiments include glass, stainless steel, aluminum, PET, PBT, PTFE,ePTFE, and BAREX®. Non-limiting examples of absorption element materialsfor such embodiments include PE and PP.

A delivery enhancing compound source may in some embodiments be, or bein communication with, a delivery enhancing compound reservoir. In someembodiments, the reservoir contains a volume of delivery enhancingcompound in liquid form with the liquid reservoir in communication withan adsorbing or absorbing delivery enhancing compound source element. Inother embodiments, the nicotine reservoir is or forms part of thedelivery enhancing compound source element. A non-limiting example ofsuch a combination source and reservoir would be a material (e.g., PE orPP) saturated with delivery enhancing compound solution. In particularembodiments, the reservoir provides sufficient delivery enhancingcompound solution to enable a delivery device to provide therapeuticallyeffective doses of nicotine over a desired time frame. Non-limitingexamples would be devices capable of delivering sufficient deliveryenhancing compound to enable delivery of 0-100 micrograms of nicotineper 35 cubic centimeter volume “puff” of gaseous carrier for a desirednumber of puffs per day (e.g. 200) over a desired number of days (e.g.1-7 days). In certain embodiments, the amount of nicotine delivered isbetween 10 and 110, 20 and 100, 50 and 100, or 40 and 60 micrograms ofnicotine per 35 cubic centimeter volume “puff.” Embodiments delivering 0micrograms of nicotine are generally intended to be the end points of agradual nicotine cessation program.

Temperature

In some embodiments of the methods, the method involves a step ofincreasing the temperature of one or more of the gaseous carrier, thenicotine source and/or the enhancer source (when present). Suchtemperature control steps are generally used to regulate or to furtherenhance the amount of nicotine delivery. In some embodiments, theincrease in temperature is used only if the nicotine levels deliveredwould generally be otherwise expected to drop below a desired minimum.In some embodiments this may be more than 20 micrograms, preferably morethan 30 micrograms, and more preferably more than 40 micrograms ofnicotine per 35 cc volume puff. For example, a common target deliveryconcentration is 40-50 micrograms nicotine per 35 cubic centimetervolume “puff” as measured by a well known technique in the nicotinedelivery field. See The FTC Cigarette Test Method for Determining Tar,Nicotine and Carbon Monoxide Yield of U.S. Cigarettes: Report of the NCIAd Hoc Committee. Smoking and Tobacco Control Monograph #7. Dr. R.Shopland (Ed.). Darby, Pa.: Diane Publishing Co, 1996. In someembodiments, generally a lower temperature is used first with thetemperature increasing over time to sustain a desired nicotine deliveryconcentration from a nicotine source. In other embodiments a constanttemperature is maintained during use. In some embodiments, thetemperature is elevated to a maximum of 100 degrees C., a maximum of 70degrees C., or the temperature is elevated to 40±5 degrees C. Forexample, pyruvic acid as a delivery enhancing compound may be heated to40 degrees C. to facilitate sustained nicotine delivery over multiplepuffs at a desired nicotine concentration range (e.g. 20-50 microgramsper puff). Temperature control may in some embodiments be effected by atemperature control element. Such elements may be any known mechanismcapable of achieving the desired target temperature for the gaseouscarrier, the nicotine and/or the delivery enhancing compound(s).Particular examples of temperature control elements are illustratedbelow in the exemplary devices provided.

Devices

The methods described herein are generally carried out using speciallyadapted delivery devices configured to carry out the methods describedherein during device operation. One of skill in the art will be able todesign and produce a variety of delivery devices using the foregoingguidance. The Inventors however provide herein a number of deliverydevice configurations to further illustrate the methods herein and theirpractical application by way of specific examples. The gaseous carrierdelivered to a device user can include a therapeutically effective doseof nicotine for smoking cessation, harm reduction and/or substitution.Preferred delivery device embodiments are pulmonary delivery systems.Pulmonary delivery systems have the ability to deliver consistent doseswith suitable particle-size and low particle-size variability to thedeep lung. Of the various non-invasive drug delivery technologiesavailable, including nasal, transdermal, buccal, and needle-freeinjections, pulmonary delivery offers unique potential for precise dosetitration, rapid absorption, and high bioavailability to deliver noveltherapeutics and improve delivery of existing compounds.

MODES FOR CARRYING OUT THE INVENTION

Screening for a Suitable Experimental Design for Nicotine AerosolFormation

Several experimental designs were tested as described below to evaluatethe generation of aerosol particles by allowing acid vapor to reactinstantly with base vapor.

Experiment #1: Hydrochloric Acid and Ammonia were Used to Generate aMixture of Vapors in a “Y” Shaped Tube that was then Passed OverNicotine Free Base

Objective:

The aim was to evaluate the effectiveness of a chemically robustacid/base system to generate an aerosol of sufficient characteristics toaerosolize nicotine free base.

Experimental Design:

The experimental design included two identical glass test tubes (Tube Acontained 5 ml of hydrochloric acid (HCl) and Tube B contained 5 mlammonia (NH₃)) connected through a “Y” shape tube designed to allow forthe vapors from the two test tubes to be admixed instantly in the “Y”shape tubing and then passed over nicotine free base using a ControlledPuff Volume Apparatus, CPVA (40 cc air at 2 seconds' duration (3-secondinterval) for 100 times (100 puffs)). The admixture of HCl and NH₃vapors produced a white, dense and visible cloud.

Results:

TABLE 1 Amount of Nicotine Obtained After Passing HCl and NH₃ OverNicotine Sample ID Nicotine(μg)/sample Nicotine(μg)/puff HCl and NH₃only 0 0 Nicotine, HCL and NH₃ 3796.265 37.963 Nicotine only 1291.92412.919

Discussion:

The use of hydrochloric acid, ammonia and nicotine resulted insignificant nicotine delivery vs. nicotine only, as shown in Table 1.However, due to the chemical reactivity and corrosive nature of the acidand base chosen for this experiment, alternative constituents wereevaluated that are more amenable to human use such as non-corrosive acidalternatives, including volatile and low-volatility organic acids (e.g.,fatty acids).

Experiment #2: Screening for Suitable Acid Candidates for Use in theDevelopment of Acid Over Nicotine Base Aerosol Delivery Arrangement

Objective:

The objective of this experiment was to evaluate a series of acidcandidates for their ability to admix with nicotine free base to form anaerosol suitable for pulmonary delivery. The superior candidates whichcreated aerosols containing the greatest mass of nicotine free basereported as μg/puff were selected for further evaluation. Volatilecarboxylic acids were selected as the organic acid of choice due totheir relative high volatility and to the fact that they areconstituents of cigarettes and other commercial products for humanconsumption such as food additives, flavoring agents and sweeteningagents.

Experimental Design:

Two identical rectangular glass chambers measuring 4 cm×2 cm×1 cm eachcontained two inlet/outlet ports extending externally through the top ofthe chamber before turning 90° away from the center of the chamber.These ports were positioned on opposite sides and near the edge of thechambers. Internally, these ports consisted of a hollow glass tube thatextended to near the bottom of the chamber. The purpose of these portswas to provide a controlled pathway for the movement of air across avolume of nicotine free base (chamber “B”) or candidate acid (chamber“A”). For this experiment chamber B was filled with 200 μL nicotine freebase and chamber A was filled with 200 μL pyruvic acid. The volumes ofnicotine free base and pyruvic acid were added by Eppendorf pipette.Neat nicotine free base and neat pyruvic acid were stored at 4° C. andunder Nitrogen gas. The working volumes of the nicotine free base andpyruvic acid were stored under refrigerated conditions but not undernitrogen. The working volumes were brought to room temperature beforetransferring to the chambers. A temperature probe was used to verifythat the working volumes had reached room temperature. A filling portalwas crafted into each chamber and positioned on the top center panel andwas used for filling the chambers with the appropriate reactants. Oncethe appropriate volume was added to the individual chamber, the portalwas sealed using a plug of PARAFILM® that was covered with TEFLON® tape.The chambers were then connected sequentially using TEFLON® tubing,secured by PARAFILM®. The outlet from Chamber B was then connected byTYGON® tubing to a filter holder containing a Cambridge filter (44 mmdiameter) used to collect the reaction product. See Pillsbury H C,Smoking machine parameters for collection of total particulate matterand gases from low ignition-potential cigarettes. Under contract to theU.S. Consumer Product Safety Commission # CPSC-S-92-5472 I i Mar. 14,1993. The opposing side of the filter housing was connected to a 100 ccsyringe by TYGON® tubing. The syringe was affixed to an automated systemmaking up the Controlled Puff Volume Apparatus (CPVA). For detailedmethodology, See Levin E D, Rose J E and Behm F. Controlling puff volumewithout disrupting smoking topography. Behavior Research MethodsInstruments & Computers, 21:383-386, 1989, the teachings of which areincorporated by reference herein. The total time to prepare the set-upfrom filling the first chamber to initiating the first sampling intervalwas approximately 5 minutes. The CPVA was programmed to pull a volume of35 cc air at 2 seconds duration (30 second intervals) for 20 times (20puffs). The filled chambers were immersed at half height into a waterbath and were allowed to equilibrate at 70° C. for 10 minutes prior tosampling.

Prior to the evaluation of the candidate acids, a control experiment wasconducted in which only the nicotine free base was kept in a chamber andnicotine vapors were pulled through a Cambridge filter for 20 times (20puffs of 35 cc air in 2 seconds duration and 30 seconds puff interval).All the samples were quantified by Gas Chromatography (GC) utilizing aNPD (nitrogen phosphorous detector).

Results:

The following table shows the results of the acid screen as well as thecontrol experiment. Results are reported by the amount of nicotinemeasured in each puff.

TABLE 2 Nicotine Delivery of Acid Over Base at ~70° c. Sample IDNicotine(μg)/puff Nicotine Control 46.12 4-Methyl-2-oxovaleric acid overNicotine 281.39 Isovaleric acid over Nicotine 25.00 Caprylic acid(Octanoic acid) over Nicotine 29.44 2-Oxooctanoic acid over Nicotine90.48 Glycolic acid over Nicotine 35.32 Caproic acid over Nicotine 14.97Levulinic acid over Nicotine 39.93 2-Oxovaleric acid over Nicotine297.75 Propionic acid over Nicotine 09.68 Pyroligneous acid overNicotine 32.54 2-Mercaptopropionic acid over Nicotine 19.29 4-Pentenoicacid over Nicotine 24.92 2-Nonenoic acid over Nicotine 39.84 Geranicacid over Nicotine 40.54 3-Methyl-2-oxovaleric acid over Nicotine 363.892-Methyl-4-pentenoic acid over Nicotine 26.03 3-Cyclohexane-1-carboxylicacid over Nicotine 48.24 Glyoxylic acid over Nicotine 35.17 Lactic acidover Nicotine 39.88 Oleic acid over Nicotine 48.45 Trimethylpyruvic acidover Nicotine 26.69 Pyruvic acid over Nicotine 362.283-Methyl-2-oxobutanoic acid over Nicotine 213.99

Discussion:

The experimental results show that at approximately 70° C.,3-Methyl-2-oxovaleric acid over nicotine delivers the greatest amount ofnicotine (363.89 μg/puff), followed by Pyruvic acid (362.28 μg/puff),2-Oxovaleric acid (297.75 μg/puff), 4-Methyl-2-oxovaleric acid (281.39μg/puff), 3-Methyl-2-oxobutanoic acid (213.99 μg/puff) and 2-Oxooctanoicacid 90.48 μg/puff. These candidates were evaluated under ambientconditions as described in the following experiment.3-Methyl-2-oxovaleric acid, Pyruvic acid, 2-Oxovaleric acid,4-Methyl-2-oxovaleric acid, 3-Methyl-2-oxobutanoic acid and2-Oxooctanoic acid represent the genus of carboxylic acids termed“2-Keto acids” or “Alpha-Keto acids.”

Experiment #3: Evaluation of Leading Acid Candidates Under AmbientTemperature

Objective:

The objective of this experiment was to assess which of the leading acidcandidates selected from the experiment described above will deliver thegreatest amount of nicotine under ambient conditions.

Experimental Design:

The current experiment was carried out as described in the previousexperiment except that the glass chambers were not immersed in a heatedwater bath, but sampled at ambient temperature. Individual experimentswere carried out using the selected acid candidates:3-Methyl-2-oxovaleric acid, Pyruvic acid, 2-Oxovaleric acid,4-Methyl-2-oxovaleric acid, 3-Methyl-2-oxobutanoic acid and2-Oxooctanoic acid. For each experiment a different acid was placed inChamber A as in the previous experiment with nicotine free base inChamber B. A nicotine free base control experiment was also conducted asin the previous experiment.

Results:

The following table shows the results of the assessment of the leadingacid candidates sampled under ambient conditions. Results are reportedas the amount of nicotine measured in each puff.

TABLE 3 Nicotine Delivery Using Selected Acids Over Base (AmbientTemperature) Sample ID Nicotine(μg)/puff Nicotine base control 8.763-Methyl-2-oxovaleric acid over nicotine 12.93 Pyruvic acid overnicotine 44.68 2-Oxovaleric acid over nicotine 18.964-Methyl-2-oxovaleric acid over nicotine 13.63 2-Oxooctanoic acid overnicotine 04.46 3-Methyl-2-oxobutanoic acid over nicotine 18.65

Discussion:

The data from ambient temperature shows that the Pyruvic acid is thesuperior candidate to form nicotine aerosol with the delivery of 44.68μg/puff.

Experiment #4: Assessment of Leading Acid Candidates from the Previous70° C. and Ambient Temperature Experiments (Experiment 2 and 3Respectively) Utilizing the Prior Art Design for Aerosol Generation

Objective:

The objective of this experiment was to compare the prior artconfiguration to the sequential orientation of acid and base todetermine which yields higher nicotine delivery. The two leading acidcandidates which generated similar nicotine delivery at 70° C. and oneacid candidate which delivered the highest amount of nicotine underambient temperature (from Experiments #2-3) were tested under 70° C. andambient conditions, respectively.

Experimental Design:

In this experiment, two identical rectangular glass chambers exactlylike those used in Experiment #2 were employed. Chamber A contained 200μL of the leading acid and chamber B contained 200 μL of nicotine freebase. The two chambers were connected via a “Y” shaped glass connectorwhich was then connected to the same PTFE housing containing a Cambridgefilter as described previously. The vapors from the tubes were allowedto be admixed instantly in the “Y” shaped glass connector upon pulling avolume of 35 cc air in 2 seconds duration (30 seconds interval) for 20times (20 puffs) using a controlled puff volume apparatus (CPVA). Forthe elevated temperature experiments, the acid and nicotine chamberswere immersed at half height into a water bath with a water temperatureof approximately 70° C. The chambers were allowed to equilibrate for 10minutes prior to sampling. For the ambient room temperature experiments,both the chambers were placed on a laboratory bench. The collectedsamples were analyzed for nicotine using Gas chromatography with aNitrogen Phosphorous detector.

Results:

The following table shows the results of the assessment of the leadingacid candidates sampled at an elevated temperature (approximately at 70°C.) and ambient conditions and employing prior art systems; alsoreported for comparison are the results using a sequentialacid-over-base design (from Experiments #2-3). Results are reported asthe mass of nicotine measured in each puff.

TABLE 4 Nicotine Delivery Using a “Y” Shaped Design (Prior Art)Nicotine(μg)/puff Prior Art Sequential Sample ID (Y-Connector) Design At~70° C. 3-Methyl-2- 11.50 363.89 oxovaleric acid and nicotine Pyruvicacid and 23.00 362.28 nicotine At ambient room temperature Pyruvic acidand 3.26 44.68 nicotine

Discussion:

Based on the current data the nicotine delivery in the prior art designis significantly lower than the sequential design and hence thesequential design is the superior method for the delivery of nicotineaerosol.

Experiment #5: Effectiveness of a Sequential Arrangement of an AcidReservoir and a Base Reservoir to Provide an Acid Over Base Environmentin the Development of an Aerosol Plume with Sufficient Concentrations ofNicotine

Objective:

The objective of this experiment was to determine the influence of thearrangement of the acid and base reservoirs in sequence allowing theacid vapors to be lifted into the nicotine free base chamber and overthe nicotine to generate a plume cloud with sufficient quantities ofnicotine free base. Pyruvic acid was selected for use in thisexperiment.

Experimental Design:

The experimental design was the same as in Experiment #2. Thisexperiment was divided into two parts, A and B. The first part, A,involved the assessment of the use of 200 μL each of nicotine free baseand pyruvic acid in separate chambers collected over 3 samples (20 puffsper sample). The second part of the experiment (part B) involved acomparison of the above system tested under ambient and 40° C.conditions to evaluate the effect of mild heat on aerosol formation andnicotine delivery.

Results (Part A):

The following tables show the results of the pyruvic acid over nicotinefree base experiment under ambient conditions (part A). Results arereported by the total mass of nicotine and the amount of nicotinemeasured in each puff.

TABLE 5 Nicotine Delivery of Acid Over Base Total Nicotine NicotineSample ID (μg)/sample (μg)/puff Pyruvic acid over Nicotine 782.16 39.11free base-1 Pyruvic acid over Nicotine 623.02 31.15 free base-2 Pyruvicacid over Nicotine 533.73 26.69 free base-3 Mean 32.31 (19.5%)(Coefficient of Variation (CV))

Discussion (part A):

These results indicate that there is an overall decline in nicotineyield from the first sample to the last, by about 32%.

Results (Part B)

The following tables show the results of the pyruvic acid over nicotinefree base experiment at 40° C. Results are reported by the total mass ofnicotine and the amount of nicotine measured in each puff.

TABLE 6 Nicotine Delivery of Acid Over Base at 40° C. Total NicotineNicotine Sample ID (μg)/sample (μg)/puff Pyruvic acid over Nicotine2341.09 117.05 free base-1 Pyruvic acid over Nicotine 2141.20 107.06free base-2 Pyruvic acid over Nicotine 2137.92 106.90 free base-3 Mean(CV) 110.337 (5.3%)

Discussion (Part B):

A 3 to 4 fold increase in the mass of Nicotine/puff was observed underheated conditions when compared to ambient conditions. Further, thecoefficient of variation significantly improved to about 5% representinggood control of the delivery dynamics. Moreover, there was nosignificant decline in nicotine delivery across puffs.

Experiment #6: Investigation of Nicotine Aerosol Formation and Deliveryby Using the Sequential Set up with Pyruvic Acid in aMiniaturized/Cigarette Sized Device (8 cm long and 8 mm ID)

Materials and Method

Matrix Materials Used:

Air-freshener wick samples made of a blend of PE and PP fibers (sold asX-40495 fiber from Porex Technologies) were used as a matrix upon whichpyruvic acid was loaded and GORE™ Medical Membrane (pore size of 0.2micron) consisting of an expanded PTFE medical membrane with a non-wovenPET membrane support (sold as SMPL-MMT314 from W.L. Gore & Associates,Inc.) was used as a matrix to load nicotine free base. The membranesheet was rolled into a straw configuration to provide a polyester innerwall and TEFLON® outer wall having approximate dimensions of 1.5 mm IDand cut into 4cm long pieces.

Experimental Design:

A piece of air-freshener wick was loaded with 180 μL of pyruvic acid(pyruvic acid source element) and the inner walls (polyester side) ofthree pieces of the 4cm long and 1.5 mm ID rolled medical membrane werecoated with 90 μL (3×30 μL) of nicotine free base. The air freshenerwith loaded pyruvic acid was inserted into the distal end of 8 mm ID and9 cm long clear TEFLON® tube and the three pieces of the medicalmembrane with nicotine free base were inserted tightly into a TEFLON®washer which had three holes (nicotine source element). The nicotinesource element was inserted into the 9 cm long, 8 mm internal diameter(ID) TEFLON® tube with the pyruvic acid source element leaving a gapbetween the pyruvic acid source element and nicotine source element of 2cm. The arrangement of the source elements was in such a way that ameasured volume of air (35 cc at 2 sec duration and 30 second puffinterval for 20 times) pulled by automated syringe pump traveled firstthrough the pyruvic acid source element and then through the nicotinesource element to form an aerosol. The proximal end of the device wasconnected to a controlled puff volume apparatus (CPVA) containing aCambridge filter (to collect aerosol product). For the elevatedtemperature (40° C.) experiment, the 9 cm long device (which had bothpyruvic acid and nicotine source elements) was completely immersed in awater bath and equilibrated for 10 minutes prior to sampling. Theambient condition experiment was carried out by placing the chambers ona laboratory bench.

Results:

The samples were analyzed for nicotine content and reported in Table 7and Table 8.

TABLE 7 Nicotine Delivery in a Miniaturized Device Experiment at ~40°Nicotine Sample ID (μg/puff) Pyruvic acid in air-freshener wick over103.58 nicotine in three rolled pieces of medical membrane

TABLE 8 Nicotine Delivery in a Miniaturized Device Experiment at AmbientTemperature Nicotine Sample ID (μg/puff) Pyruvic acid in air-freshenerwick over 29.20 nicotine in three rolled pieces of medical membrane

Discussion:

The data indicates that when both the acid and base were loaded onto amatrix, in this case, air-freshener wick for acid and medical membranefor nicotine free base, a comparable nicotine delivery was obtained aswith the previous experimental apparatus used in Experiment 5. Inaddition, the ˜40° C. condition showed a significantly higher amount ofnicotine delivery (approximately threefold) when compared to the ambientcondition.

Exemplary Devices Adapted for Use with the Methods Herein

Delivery devices of some embodiments comprise a housing which simulatesa tobacco smoking article. The housing may simulate the size, shape,and/or configuration of any article used for smoking tobacco articles.Non-limiting examples of smoking articles according to the presentinvention include cigarettes, cigars, cigarillos and pipes.

Delivery devices of some embodiments comprise a housing which simulatesa pharmaceutical inhalation device. The housing may simulate the size,shape, and/or configuration of any pharmaceutical device used forinhalation. Non-limiting examples of pharmaceutical inhalation devicesaccording to the present invention include, metered dose inhalers,pressurized metered dose inhalers, dry powder inhalers, nebulizers andliquid based inhalers.

Exemplary Device 1

Directing attention to FIG. 1, a device for the formation and deliveryof a nicotine aerosol to a user according to an embodiment of thepresent invention is shown. Specifically, nicotine inhaler 10 having thesize, shape, and appearance of a cigarette is shown. Nicotine inhaler 10consists of housing 12, which has an elongated cylindrical shape and ishollow. To allow for a gaseous flow through inhaler 10, housing 12contains gaseous inlet 14 and gaseous outlet 16 on opposing ends.

The portion of housing 12 between gaseous inlet 14 and gaseous outlet 16is divided into three compartments capable of holding a first, second,and/or third substance. The first, second, or third substance cancomprise a vapor forming medicament, such as nicotine.

As illustrated in FIG. 2, nicotine inhaler 10 includes first compartment18, second compartment 20, and third compartment 22. Nicotine,preferably in the free base form, may be placed in any of the threecompartments. For example, nicotine can be placed within secondcompartment 20. A suitable delivery enhancing compound, such as an acid,is placed within first compartment 18. Any suitable acid can be used.For example, pyruvic acid can be placed within first compartment 18.Pyruvic acid is a volatile substance which has a substantial vaporpressure at room temperature. As such, any free space within firstcompartment 18 will be filled to some degree with pyruvic acid vapor,that is, gaseous pyruvic acid. Although the vapor pressure of nicotineis less than that of pyruvic acid, nicotine is also a volatilesubstance. In the same manner, any free space within second compartment20 will be filled to some degree with nicotine vapor.

It should be appreciated that the pyruvic acid is held within firstcompartment 18 on a delivery enhancing compound source element (notshown) and nicotine is held within second compartment 20 on a nicotinesource element (not shown). Additionally, a third substance may be heldon a third source element (not shown) within third compartment 22.Furthermore, one or more of the source elements may be integral with orpart of compartments 18, 20, and 22, respectively.

The delivery enhancing compound source element can be any size and shapethat allows a gaseous stream to contact a vapor of the acid and passthrough first compartment 18. The nicotine source element can be anysize and shape that allows a gaseous stream to contact a vapor ofnicotine and pass through second compartment 20. The third sourceelement can be any size and shape that allows a gaseous stream tocontact a third substance and pass through third compartment 22.

The delivery enhancing compound source element can be composed of anysuitable material capable of holding the acid on its surface whileallowing the acid vapors to permeate into the surrounding area. Thenicotine source element can be composed of any suitable material capableof holding nicotine on its surface while allowing the nicotine vapors topermeate into the surrounding area. The third source element can becomposed of any suitable material capable of holding a third substance.In specific embodiments, the suitable material holds the third substanceon its surface while allowing the vapor of the third substance topermeate into the surrounding area.

Preferably, a suitable source element material is inert to any substanceto be placed on its surface. Additionally, a suitable material ispreferably adsorbing with respect to any substance to be placed on itssurface such that said substance is adsorbed on the surface of thematerial. Although a material having both absorptive and adsorptivecharacteristics can be employed, a material capable of holding thedelivery enhancing compound(s), nicotine and/or third substance throughadsorption is preferred. Non-limiting examples include glass, aluminum,PET, PBT, PTFE, ePTFE, and BAREX®.

The adsorptive material may function via capillary action tocontinuously present the substances to the surface of the adsorbingmaterial.

Third compartment 22 can contain a purifying agent. For example,activated charcoal can be incorporated into third compartment 22 usingany method which provides the resulting third compartment 22 with gaspurification capability. Suitable methods are well-known in the art. Forexample, the charcoal may be placed within third compartment 22 as acharcoal plug or filter.

In operation, a user puffs on gaseous outlet 16 of nicotine inhaler 10,as shown in FIG. 3. The partial vacuum created by the puffing actiondraws a gaseous stream into housing 12 through gaseous inlet 14. Thegaseous stream enters first compartment 18 and captures a vapor of theacid by passing over the pyruvic acid source element held in firstcompartment 18. The gaseous stream that exits first compartment 18 andsubsequently enters second compartment 20 is an acid-containing gaseousstream. The acid-containing gaseous stream generates a stream ofnicotine-containing particles by passing over the nicotine held by thenicotine source element in second compartment 20. The stream ofnicotine-containing particles passes through third compartment 22 andexits through gaseous outlet 16 into the mouth of the user. Anyunreacted acid is removed from the stream of nicotine-containingparticles via the activated charcoal filter in third compartment 22. Itshould be appreciated that pyruvic acid could be held on a first elementin first compartment 18 and/or nicotine could be held on a secondelement in second compartment 20. Additionally, a third substance, suchas a purifying or flavoring agent, may be held on a third element inthird compartment 22. Furthermore, the first, second, and third elementsmay be integral with or part of compartments 18, 20, and 22,respectively.

Exemplary Device 2

This exemplary device is illustrated and described by reference to FIGS.4-6. In FIG. 4, the elements of the device are shown in an assembly flowchart. The delivery enhancing compound source 30 and the nicotine source40 are optionally manufactured and stored as independent componentsgenerally having frangible barrier end caps 35 and 45 heat sealed on theends. These two elements 30 and 40 are inserted into a first housing 50.First housing 50, containing delivery enhancing compound source 30 andthe nicotine source 40, is then inserted into a second housing 100. Thehousings 50 and 100 and the elements 30 and 40 are generally extrudedplastic tubing. Also inserted into second housing 100 is heating element95. The heating element 95 is generally a thin flexible heating foilwhich is configured to wrap around housing 50 and to contact housing 50sufficiently to enable heating the delivery enhancing compound source 30and/or the nicotine source 40 to a desired temperature (e.g. 40 degreesC.). Heating element 95 is also adapted to contact battery 130 to supplypower to the heating foil element 95.

Filter element 80 is adapted to insert and snap-lock into second housing100. Filter element 80 comprises a filter cavity 75 adapted to contain afilter 70. Filter 70 is generally a charcoal filter and may containadditional volatile compounds such as flavoring agents commonly used incigarettes. Filter element 80 may have foil seal 150 to seal theassembled pre-use configuration 160.

Filter element 80 has aperture 90 which aligns with aperture 110 ofsecond housing 100. When assembled, air inlet 140 is formed. The filterelement 80 and the second housing 100 are configured to permit rotationto select a desired air inlet 140 aperture dimension. The air inlet 140forms when filter element 80 is fully inserted into second housing 100as shown by 170. The full insertion of filter element 80 also forcespenetrating elements 60 through frangible barriers 35 and 45 to unsealthese elements for an unobstructed air flow pathway from air inlet 140to particle delivery aperture 180.

FIG. 5 shows various alternative structures for delivery enhancingcompound source 30 and the nicotine source 40. The delivery enhancingcompound in this configuration is generally a volatile acid which may beheld by adsorption onto sintered plug 310, PE wick 320, a fiber bundle330, a mutilumen tube 340 or 350, woven or non-woven PET, PBT, or PETGfabric material 360, PET static mixer 370, or a helical path wrapped innonwoven material 380.

FIG. 6 shows some embodiments of this device where the device comprisesa reusable portion 210 and a disposable portion 200. Referring to FIG.1, disposable portion 200 comprises the delivery enhancing compoundsource 30 and the nicotine source 40, the first housing 50, and thefilter element 80. The reusable portion 210 comprises second housing100, heating element 95 and battery 130.

Exemplary Device 3

A fully reusable exemplary device is illustrated by FIG. 7. Twoalternative configurations are illustrated wherein portion 410 and 420or 430 and 440 are reversibly attachable. For example the portions maybe extruded plastic adapted and dimensioned to permit repeatedsnap-locking and removal. The removable portions 420 or 440 compriseapertures 430 and 440 for communication with delivery enhancing compoundsource 445 and nicotine source 435. Portions 420 or 440 insert intorecharging element 450 through aperture 460. Elements 470 are sealingo-rings to seal off the reservoir when recharging delivery enhancingcompound source 445 and nicotine source 435. Loading apertures 480 and490 are configured to communicate with delivery enhancing compoundsource 445 and nicotine source 435 once portion 420 is seated inrecharging element 450. In some embodiments, gravity drives flow fromdelivery enhancing compound reservoir 500 and nicotine reservoir 510 todelivery enhancing compound source 445 and nicotine source 435,respectively. In some embodiments, the flow from the reservoirs to thesources is in part due to wicking of the reservoir liquid by the sourceelements. For example, delivery enhancing compound source 445 andnicotine source 435 may comprise a source element containing PET tocreate rapid wicking and thus reloading of sources 445 and 435.

Exemplary Device 4

Another exemplary device is illustrated by FIGS. 8 and 9. This exemplarydevice is rechargeable and configured to simulate a typical cigarettepack. Referring to FIG. 8, delivery device 600 is configured to insertinto recharging unit 610 through storage aperture 620 and rechargingaperture 630. When fully seated in the recharging unit 610 on rechargingelement 640, the device 600 is recharged with delivery enhancingcompound and/or nicotine.

FIG. 9 shows the recharging element 640 in detail. In FIG. 9A, injectionelement 650 having loading apertures 660 and 670 is in flowcommunication with reservoirs 720 and 730 through metered dose actuatorpumps 680 and 690 and tubes 700 and 710. In FIG. 9B, delivery device 600is shown seated in recharging unit 640. Injection element 650 passesthrough a recharging aperture at the base of the delivery device andinto said device so that apertures 660 and 670 are in communication withnicotine source element 740 and delivery enhancing compound sourceelement 750. In FIG. 9C, the delivery device 600 is further insertedinto recharging unit 640 to actuate the pumps 680 and 690 to delivermetered doses 770 of nicotine and 760 of delivery enhancing compoundthrough apertures 660 and 670, respectively, and into nicotine sourceelement 740 and delivery enhancing compound source element 750,respectively.

Exemplary Device 5

This exemplary device is illustrated by FIG. 10. This deviceconfiguration has a heating unit 850 external to the delivery device800. Upon insertion of delivery device 800 into heating unit 850,electrical contacts 840 are in contact with leads 825 which permitbattery 830 to heat foil heating element 860 to control the temperatureof the delivery enhancing compound source 870 and nicotine source 880to, e.g., 40±5 degrees C. An alternative configuration places theheating foil 860 within the delivery device 800, as shown in FIG. 4.

Exemplary Device 6

The foregoing exemplary devices are generally configured to simulate acigarette and cigarette pack. The delivery devices suitable for use withthe methods herein are readily configured in a variety of ways. Anexample is illustrated in FIG. 11. This exemplary device simulates ametered dose inhaler commonly used for pharmaceutical delivery ofinhaled medicaments. Delivery device 900 comprises a first housing 910and a second housing 920. Second housing 920 is removable (FIG. 11A) andin (FIG. 11B) for recharging or replacement of battery 990. The inposition brings electrical contact 1050 and 1060 into communicationthereby allowing battery 990 to heat foil heating element 950 to in turncontrol the temperature of delivery enhancing compound source 960 andnicotine source 970. Air intake actuator 930 is configured to slideanywhere from the position in FIG. 11A to 11B. Power for heating foilelement 950 may be optionally turned on or off using air intake actuator930 or a separate switching means (not shown). Air intake aperture 940may then be opened to a selected degree thereby controlling the volumeof air per inhalation and consequently the amount of nicotine. Thisfeature is analogous to adjustable air intake aperture 140 of FIG. 1. Inoperation, air is drawn through air intake aperture 940, down to chamber1000, through conduit 1010, through the delivery enhancing compoundsource 960 where delivery enhancing compound is captured in the airflow. For example, pyruvic acid vapor may be emanating from a PET sourceelement having liquid pyruvic acid adsorbed thereon. This vapor is movedby the air flow through conduit 1020 into the nicotine source 970. Herethe delivery enhancing compound increases the concentration of nicotinein the airflow relative to the amount of nicotine vapor that would becontained in the same volume of air flow in the absence of the deliveryenhancing compound. In the case of pyruvic acid, nicotine pyruvate saltparticulates may be formed to enhance delivery of nicotine to a subject.Delivery may be further enhanced by elevating the temperature of, e.g.,pyruvic acid and nicotine, by means of heating element 950 to increasethe vapor pressure of those compounds. The airflow containing nicotinenow moves through conduit 1030, through charcoal filter 980 and out theinhalation aperture 1040.

FIGS. 11C and D illustrate an embodiment of the exemplary inhaler device900 wherein a portion of the device having the delivery enhancingcompound source 960 and nicotine source 970 in a disposable housing 1050which is configured to slide into and out of reusable housing 1060 toform a device functionally identical to device 900. Battery housingelement 1070 is detachable from disposable element 1050 and thusreusable with portion 1060 and a replacement element 1050.

Exemplary Device 7

FIG. 12, A-C illustrates another configuration of an inhalation device.In this configuration, the delivery enhancing compound source and thenicotine source are the lower and upper surface areas of split innertube 1100. In the usage configuration 12A, an impermeable cover 1110 isin place over nicotine reservoir 1120 and delivery enhancing compoundreservoir 1130. The impermeable cover 1110 reduces evaporative loss fromthe reservoirs and physically separates the reservoirs from the splitinner tube 1100. In use, bottom housing 1180 is pushed into main housing1190 until first catch spring 1140 is locked in the position shown in12B. This places the reservoirs 1120 and 1130 in parallel proximity tothe split inner tube 1100. Shown in 9C, the bottom housing 1180 isfurther inserted into main housing 1190 until second catch spring 1150is locked in the position shown in 12C. In this third position, pressureelements 1160 squeeze split inner tube 1100 to force wall 1170 intocontact with reservoirs 1120 and 1130. This action forces nicotine anddelivery enhancing compound (e.g. pyruvic acid) onto the inner surfaceof wall 1170 to recharge this surface as the nicotine source and thedelivery enhancing compound source.

Exemplary Device 8

FIG. 13 shows a variant of the device of FIG. 12. In this version,bottom housing 1250 is depressed against conical spring 1230 to forcethe nicotine reservoir 1210 and the delivery enhancing compoundreservoir 1220 through reservoir cover 1200 and into contact with theinner surface of conical inner tube 1240, thereby coating the surfacewith nicotine and delivery enhancing compound (FIG. 13B).

Exemplary Device 9

FIG. 14 shows another version of the device of FIG. 12. In this version,outer housing 1300 is contiguous with the moving components being switch1310 and the various internal elements shown. Switch 1310 is connectedto source seating element 1330 by a connecting bar 1320. As switch 1310is moved up, rigid seating element 1330 moves along pole 1360. At thecharging position, reservoir elements 1340 and 1350 are brought intocontact with flexible element 1370 which is also brought into contactwith rigid seating element 1330. Rigid seating element 1330 isdimensioned to squeeze flexible elements 1370 into contact withreservoir elements 1340 and 1350 in the final portion of the slidingmotion (FIG. 14B). This action coats the upper portion of flexibleelement 1370 with, e.g., nicotine base solution from reservoir 1350 andthe lower portion of flexible element 1370 with pyruvic acid from 1340to create a nicotine source and a delivery enhancing compound source,respectively. The top surface of reservoir 1350 may be covered by animpermeable material to limit the amount of volatilization of medicamentand delivery enhancing compound from the reservoirs when in theoperational position (FIG. 14A). A circular flap of flexible,impermeable material may extend from elements 1320 or 1330 to close offthe volume below reservoir 1350 and further limit volatilization. Incharging position (FIG. 14B) the flap would be forced down and away fromthe reservoirs by flexible element 1370.

Exemplary Device 10

FIG. 15 shows another delivery device configuration. FIG. 15A shows thedevice 1400 in use mode. Air moves from intake 1410 past deliveryenhancing compound source 1500, nicotine source 1490 and through outlet1415. The nicotine and delivery enhancing compound are coated onto theside walls of their respective sources. To recharge the sources,delivery enhancing compound reservoir 1430 and nicotine reservoir 1420are provided. Switch 1460 may be actuated to recharge the sources. Uponactivation by switch 1460, base 1510 is moved along guide rod 1470toward delivery enhancing compound source 1500 and nicotine source 1490.Shown in FIG. 15B, upon contact with the delivery enhancing compoundsource 1500, the nicotine source 1490 and the upper stop element 1480,impermeable caps 1440 and 1450 compress reservoirs to force deliveryenhancing compound and nicotine out onto the surfaces of the sources1490 and 1500. The reservoirs in this device may be made of any flexibleadsorbing or absorbing material capable of holding the nicotine ordelivery enhancing solutions. The reservoirs will generally be motivatedback down guide pole 1470 automatically after recharging the sources,thus making the device a conveniently operated “one click” device. Themovement of the reservoirs may be achieved by any convenient means. Forexample, a motive wire 1520 may be provided within a groove on guidepole 1470. The motive wire 1520 may be attached to base 1510 and movesup and down the guide pole 1470 by a motor rotated element (not shown).In some versions of this device configuration, the top outer portion ofdevice 1400 may be rotated to define the size of inlet 1410 analogous toelement 140 shown in FIG. 4.

INDUSTRIAL APPLICABILITY

The methods and devices herein are useful for the therapeutic deliveryof nicotine for smoking cessation, harm reduction and/or substitution.In addition, the devices and methods herein are useful as analternative, general nicotine delivery system in place of tobacco basedproducts. The methods and devices herein are further useful for thedelivery of other medicaments as described herein.

Although the present invention and its advantages have been described indetail, it should be understood that various changes, substitutions andalterations can be made herein without departing from the spirit andscope of the invention as defined by the appended claims. Moreover, thescope of the present application is not intended to be limited to theparticular embodiments of the process, machine, manufacture, compositionof matter, means, methods and steps described in the specification. Asone of ordinary skill in the art will readily appreciate from thedisclosure of the present invention, processes, machines, manufacture,compositions of matter, means, methods, or steps, presently existing orlater to be developed that perform substantially the same function orachieve substantially the same result as the corresponding embodimentsdescribed herein may be utilized according to the present invention.Accordingly, the appended claims are intended to include within theirscope such processes, machines, manufacture, compositions of matter,means, methods, or steps.

All references and other information cited to, or otherwise identifiedherein, are hereby incorporated by reference in their entireties as ifeach had been separately so incorporated. The priority application, U.S.provisional patent application Ser. No. 60/909,302 filed 30 Mar. 2007,is also hereby incorporated by reference in its entirety.

What is claimed is:
 1. A method of delivering nicotine to a subject byinhalation the method comprising the steps of: a) first placing agaseous carrier comprising a delivery enhancing compound incommunication with a nicotine source comprising the nicotine, and b)second providing the gaseous carrier comprising the nicotine to asubject.
 2. The method of claim 1, further comprising the step ofplacing the gaseous carrier in communication with a delivery enhancingcompound source comprising the delivery enhancing compound.
 3. Themethod of claim 2, wherein the step of placing the gaseous carrier incommunication with the delivery enhancing compound source precedes thestep of placing the gaseous carrier comprising the delivery enhancingcompound in communication with the nicotine source.
 4. The method ofclaim 3, wherein the delivery enhancing compound source comprises aplurality of compartments comprising two or more precursor compounds. 5.The method of claim 4, wherein the delivery enhancing compound comprisesammonium chloride and the two or more precursor compounds includeammonia and hydrogen chloride.
 6. The method of claim 1, wherein thedelivery enhancing compound comprises an acid.
 7. The method of claim 6,wherein the acid is an organic acid.
 8. The method of claim 6 whereinthe acid is selected from the group consisting of 3-Methyl-2-oxovalericacid, Pyruvic acid, 2-Oxovaleric acid, 4-Methyl-2-oxovaleric acid,3-Methyl-2-oxobutanoic acid, 2-Oxooctanoic acid and combinationsthereof.
 9. The method of claim 1, wherein the delivery enhancingcompound interacts with the nicotine to form particles.
 10. The methodof claim 9, wherein the particles comprise particles of less than 6microns in Mass Median Aerodynamic Diameter.
 11. The method of claim 9,wherein the particles comprise particles of less than 1 micron in MassMedian Aerodynamic Diameter.
 12. The method of claim 9, wherein at leastsome of the particles are between 0.5 and 5 microns in Mass MedianAerodynamic Diameter.
 13. The method of claim 1, further comprising thestep of increasing the temperature of the delivery enhancing compound,the delivery enhancing compound source, the nicotine, the nicotinesource and/or the gaseous carrier.
 14. The method of claim 1, whereinthe gaseous carrier comprises at least 20 micrograms of nicotine in avolume of gaseous carrier provided to the subject.
 15. A deviceconfigured to be capable of carrying out the method of claim
 1. 16. Amethod of tobacco product use cessation comprising the method of claim 1and further comprising a delivery to the subject of a therapeuticallyeffective amount of nicotine to at least partially replace nicotinederived from a tobacco product.
 17. A method of treating a disease forwhich nicotine is therapeutically beneficial comprising the step ofproviding a therapeutically effective amount of nicotine by the methodof claim
 1. 18. The method of claim 17, wherein the disease is selectedfrom the group consisting of nicotine addiction, obesity, Alzheimer'sDisease, Parkinson's Disease, Ulcerative Colitis, Multiple Sclerosis andcombinations thereof.
 19. A method of tobacco product substitutioncomprising delivering nicotine to a subject by the method of claim 1 tosubstitute for nicotine derived from a tobacco product.
 20. A method oftobacco product harm reduction comprising delivering nicotine to asubject by the method of claim 1 to replace nicotine derived from aharmful tobacco product.
 21. A device for delivering nicotine or othermedicament to a subject, the device comprising a housing, the housingcomprising: a) an inlet and an outlet in communication with each otherand adapted so that a gaseous carrier may pass into the housing throughthe inlet, through the housing and out of the housing through theoutlet, the device comprising in series from inlet to outlet: b) a firstinternal area in communication with the inlet, the first internal areacomprising a delivery enhancing compound source, c) a second internalarea in communication with the first internal area, the second internalarea comprising the nicotine or other medicament source, and d)optionally, a third internal area in communication with the secondinternal area.
 22. The device of claim 21 wherein the enhancer sourcecomprises an adsorption element with the delivery enhancing compoundadsorbed thereon and/or wherein the nicotine or other medicament sourcecomprises an adsorption element with the medicament adsorbed thereon.23. The device of claim 22 wherein the adsorption element or elementscomprises at least one of glass, aluminum, PET, PBT, PTFE, ePTFE, andBAREX.
 24. The device of claim 21, further comprising a first reservoirin communication with the first internal area, the first reservoircomprising the delivery enhancing compound.
 25. The device of claim 21,further comprising a second reservoir in communication with the secondinternal area, the second reservoir comprising nicotine or othermedicament.
 26. The device of claim 21, comprising the third internalarea, the third internal area comprising a third internal area element.27. The device of claim 26, wherein the third internal area elementcomprises a purifying agent.
 28. The device of claim 26, wherein thethird internal area element comprises a flavoring agent.
 29. The deviceof claim 26, where the third internal area element comprises amedicament.
 30. The device of claim 29, wherein the medicament comprisesnicotine.
 31. The device of claim 21, wherein the housing simulates atobacco smoking product.
 32. The device of claim 31, wherein the tobaccosmoking product is a cigarette.
 33. The device of claim 21, wherein thehousing simulates a pharmaceutical inhalation device.
 34. A method ofdelivering a medicament to a subject by inhalation the, methodcomprising the steps of: a) first placing a gaseous carrier comprising adelivery enhancing compound in communication with a medicament sourcecomprising the medicament, and b) second providing the gaseous carriercomprising the medicament to a subject.
 35. The method of claim 34wherein the medicament is selected from the group consisting ofNicotine, 7-Hydroxymitragynine, Arecoline, Atropine, Bupropion, Cathine(D-norpseudoephedrine), Chlorpheneramine, Dibucaine, Dimemorphan,Dimethyltryptamine, Diphenhydramine, Ephedrine, Hordenine, Hyoscyamine,Isoarecoline, Levorphanol, Lobeline, Mesembrine, Mitragynine, Muscarine,Procaine, Pseudo ephedrine, Pyrilamine, Raclopride, Ritodrine,Scopolamine, Sparteine (Lupinidine), Ticlopidine,1,2,3,4-Tetrahydroisoquinolines, Anabasine, Anatabine, Cotinine,Myosmine, Nicotrine, Norcotinine, Nornicotine, Orciprenaline,Propranolol, Terbutaline, Nicorandil, Oxprenolol, Verapamil, Lidocaine,Epibatidine, 5-(2R)-azetidinylmethoxy)-2-chloropyridine (ABT-594),(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole (ABT 418),(±)-2-(3-Pyridinyl)-1-azabicyclo[2.2.2]octane (RJR-2429),Methyllycacotinine, Mecamylamine, Galantamine, Pyridostigmine,Physostigmine, Tacrine, 5-Methoxy-N,N-dimethyltryptamine,5-methoxy-α-methyltryptamine, Alpha-methyltryptamine, Iproclozide,Iproniazide, Isocarboxazide, Linezolid, Meclobemide,N,N-Dimethyltryptamine, Phenelzine, Phenyl ethylamine, Toloxatone,Tranylcypromine, Tryptamine and combinations thereof.
 36. The method ofclaim 34 wherein the medicament is delivered in a therapeuticallyeffective amount for a disease for which the medicament istherapeutically beneficial.
 37. The method of claim 34, wherein themedicament is an aliphatic or aromatic, saturated or unsaturatednitrogenous base in which a nitrogen atom is present in a heterocyclicring or in an acyclic chain.
 38. The medicament of claim 37 wherein themedicament has a melting point below 150° C. and/or boiling point below300° C.
 39. The method of claim 34, wherein the medicament is a TobaccoSmoke Constituent.
 40. The method of claim 34, wherein the medicament isa Nicotinic receptor agent.
 41. The method of claim 40 wherein theNicotinic receptor agent is a Nicotinic agonist.
 42. The method of claim40 wherein the Nicotinic receptor agent is a Nicotinic antagonist. 43.The method of claim 40 wherein the Nicotinic receptor agent is an Acetylcholinesterase inhibitor.
 44. The method of claim 34, wherein themedicament is an MAO-inhibitor.
 45. The method of claim 34, wherein themedicament is an Anti-asthmatic drug.
 46. The method of claim 34,wherein the medicament is an Anti-angina drug.
 47. The method of claim34, wherein the medicament is an Antiarrhythmic drug.
 48. A deviceconfigured to be capable of carrying out the method of claim 34.